PROJECT SUMMARY: Mortality rates in intensive care units (ICUs) are unacceptably high and are directly related to the duration of mechanical ventilation that is required to support patients with respiratory failure. For example, acute respira- tory distress syndrome (ARDS) is a vexing acute inflammatory lung disease requiring mechanical ventilatory support as the result of severe hypoxemia and respiratory failure. The estimated 200,000 ARDS cases/yr (U.S.) exhibit a mortality rate of 30-40% with ventilator-induced lung injury (VILI), a potent stimulus for lung inflam- mation and release of multiple inflammatory cytokines (known as cytokine storm), a significant contributor to ARDS severity and mortality. VILI may also ensue in mechanically ventilated patients with respiratory failure in intensive care units (ICUs) even when ARDS is not present. As no clinical therapeutic intervention in the ICU has significantly addressed VILI, there remains a serious unmet need for effective preventive therapies for VILI. Aqualung Therapeutics scientists have identified nicotinamide phosphoribosyltransferase (NAMPT) as a novel upstream therapeutic target in the development of VILI, and have developed human monoclonal antibodies (Fabs or fragment antigen-binding) designed to neutralize circulating extracellular NAMPT (or eNAMPT). Given the lack of approved VILI therapies, ALT seeks to improve ICU outcomes by developing the human mon- oclonal Fab, eNamptorTM, as an innovative strategy to reduce or eliminate VILI, targeting circulating eNAMPT. eNamptorTM will be given prophylactically at the time of intubation in critically ill ICU patients receiving mechanical ventilation, a marked advantage compared with prior ICU strategies. We expect that eNamptorTM will reduce or eliminate VILI incidence and severity, reduce the number of days ICU patients require mechanical ventilation, reduce healthcare costs, and improve ICU survival. With this background, the goal of this STTR Phase I/II Fast Track application is to evaluate NAMPT-neutralizing pegylated and non-pegylated human monoclonal eN- amptorTM Fab candidates for efficacy in attenuating eNAMPT-induced NFkB in vitro signaling and preclinical murine VILI in vivo models (STTR Phase I). In addition, we will conduct pharmacokinetic/pharmacodynamic and toxicology studies with lead eNamptorTM Fab candidates in rat and canine models (STTR Phase II). This STTR Phase I/II Fast Track application represents a collaboration between a biotech startup company (Aqualung Therapeutics Corporation), an academic entity (University of Arizona) and a private company (Gennova Biophar- maceutical Ltd.). Together, we will address a serious and important unmet need by validating eNamptorTM as a viable VILI therapeutic approach. We anticipate these efforts will lead to submission of a IND application to the FDA to promote eNamptorTM as a therapeutic strategy for VILI in man.